Cytochrome P4502E1 Inhibition by Propylene Glycol Prevents Acetaminophen (Paracetamol) Hepatotoxicity in Mice without Cytochrome P4501A2 Inhibition

Authors


Author for correspondence: Henrik E. Poulsen, Department of Pharmacology, Panum Institute 18-5-48, 3 Blegdamsvej, DK-2200 Copenhagen, Denmark (fax + 45 3532 7610).

Abstract

Abstract: Acetaminophen hepatotoxicity is associated with its biotransformation to the reactive metabolite N-acetyl-p-benzoquinone imine that binds to protein. Two forms of cytochrome P450, CYP2E1 and CYP1A2, have been implicated as primarily responsible for the bioactivation. To determine the relative contributions of these P450's, overnight fasted male NMRI mice were pretreated with 10 ml of 50% v/w propylene glycol/kg or fluvoxamine (10 mg/kg) at–80 and–20 min. relative to acetaminophen dosing to inhibit CYP2E1 and CYP1A2, respectively. Mice were sacrificed at 0.5 or 4 hr after a hepatotoxic dose of acetaminophen (300 mg/kg). Propylene glycol or propylene glycol plus fluvoxamine, but not fluvoxamine alone protected against acetaminophen hepatotoxicity as indicated by abolished increase in serum alanine aminotransferase activity, less depletion of hepatic glutathione and lower livenbody weight ratios. Propylene glycol inhibited the activity of CYP2E1 as indicated by 84% reduction in the clearance of 3 mg/kg dose of chlorzoxazone, whereas fluvoxamine inhibited the activity of CYP1A2 as indicated by 40% reduction in the clearance of a 10 mg/kg dose of caffeine. For this animal model, the data are consistent with the notion that hepatotoxicity is associated with bioactivation of acetaminophen by CYP2E1 but not by CYP1A2.

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